Journal Article

Rebalancing TGF‐β/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis

Ba, Qian, Sun, Mayu, Li, Weida, Wang, Wei, Li, Xiaoguang, Wang, Hui, Jiang, Zheshun, Li, Jingquan, Liu, Chaobao, Gu, Pengfei, Yang, Yang, You, Rongli

2021

Overview

Background Liver fibrosis and fibrosis‐related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor‐β (TGF‐β) is a critical mediator of chronic liver fibrosis, targeting TGF‐β isoforms and receptors lead to unacceptable side effect. This study was designed to explore the antifibrotic effect of Compound kushen injection (CKI), an approved traditional Chinese medicine formula, via a therapeutic strategy of rebalancing TGF‐β/Smad7 signaling. Methods A meta‐analysis was performed to evaluate CKI intervention on viral hepatitis‐induced fibrosis or cirrhosis in clinical randomized controlled trials (RCTs). Mice were given carbon tetrachloride (CCl4) injection or methionine‐choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF‐β/Smad signaling and typical fibrosis‐related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT‐PCR, Western blotting, RNA‐seq, immunofluorescence, and immunohistochemistry. Results Based on meta‐analysis results, CKI improved the liver function and relieved liver fibrosis among patients. In our preclinical studies by using two mouse models, CKI treatment demonstrated promising antifibrotic effects and postponed hepatocarcinogenesis with improved liver function and histopathologic features. Mechanistically, we found that CKI inhibited HSCs activation by stabilizing the interaction of Smad7/TGF‐βR1 to rebalance Smad2/Smad3 signaling, and subsequently decreased the extracellular matrix formation. Importantly, Smad7 depletion abolished the antifibrotic effect of CKI in vivo and in vitro. Moreover, matrine, oxymatrine, sophocarpine, and oxysophocarpine were identified as material basis responsible for the antifibrosis effect of CKI. Conclusions Our results unveil the approach of CKI in rebalancing TGF‐β/Smad7 signaling in HSCs to protect against hepatic fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. Our study suggests that CKI can be a candidate for treatment of hepatic fibrosis and related oncogenesis. 1. CKI ‐suppresses liver fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. 2. CKI inhibits HSCs activation by stabilizing the interaction of Smad7/TGFβR1 to rebalance Smad2/Smad3 signaling, acting as an alternative approach to target TGF‐β signaling. 3. High expression of Smad7 and low expression of TGFβR1 in HCC tumors and surrounding normal liver tissues can be tumor suppressive.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Animals / Antibodies / Antigens / Cancer therapies / Carbon Tetrachloride - toxicity / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - pathology / Cell Line / Chromatography / Clinical medicine / Clinical trials / Collagen / Compound kushen injection / Diet / Drugs, Chinese Herbal - pharmacology / Drugs, Chinese Herbal - therapeutic use / Genes / Growth factors / Hepatic Stellate Cells - cytology / Hepatic Stellate Cells - metabolism / Hepatitis / hepatocellular carcinoma / Humans / Laboratory animals / Liver - metabolism / Liver - pathology / Liver cancer / Liver cirrhosis / Liver Cirrhosis - chemically induced / Liver Cirrhosis - drug therapy / liver fibrosis / Liver Neoplasms - drug therapy / Liver Neoplasms - pathology / Male / Medicine, Chinese Traditional / Meta-Analysis as Topic / Mice / Mice, Inbred C57BL / Olive oil / RNA Interference / RNA, Small Interfering - metabolism / Signal Transduction - drug effects / Smad7 Protein - antagonists & inhibitors / Smad7 Protein - genetics / Smad7 Protein - metabolism / Smooth muscle / TGF‐β/Smad signaling / Traditional Chinese medicine / Transforming Growth Factor beta - metabolism